PubMed Health⌕ Search

Biomedical subjects

Thierry Le Chevalier

Publications and source records attributed to Thierry Le Chevalier.

At least 19 recordsLinked to original sources
PubMed2006

Erlotinib for frontline treatment of advanced non-small cell lung cancer: a phase II study.

PURPOSE: Erlotinib has proven activity in pretreated patients with advanced non-small cell lung cancer (NSCLC). We evaluated erlotinib in the frontline treatment of advanced NSCLC and assessed biological predictors of outcome. EXPERIMENTAL DESIGN: In this phase II study, chemotherapy-naive patients with stage IIIB/IV NSCLC received oral erlotinib (150 mg/d) until disease progression or unacceptable toxicity occurred. Tumor response was assessed every 6 weeks, and samples were analyzed for potential molecular markers of treatment response and survival. The primary end point was the proportion of patients without disease progression after 6 weeks of treatment. RESULTS: Fifty-three patients were eligible. The overall rate of nonprogression at 6 weeks was 52.8% (28 of 53 patients). Tumor response rate was 22.7%, with 1 complete response, 11 partial responses, and 16 cases of stable disease. Responses were seen across most patient clinical characteristics. The median duration of tumor response was 333 days; median overall survival was 391 days; and median time to disease progression was 84 days. Erlotinib was well tolerated, the main treatment-related adverse events being mild-to-moderate rash and diarrhea. Histologic material for biological studies was available in 29 cases. Four of five responders and one patient with stable disease had a classic epidermal growth factor receptor tyrosine kinase mutation. Two progressing patients exhibited epidermal growth factor receptor point mutations (one with T790M mutation), and K-ras mutations were detected in 10 nonresponders. CONCLUSIONS: Erlotinib shows significant antitumor activity in the first-line treatment of advanced NSCLC and may be a viable alternative to chemotherapy. Patient selection cannot easily be based on clinical or biological variables.

Administration, Oral↗
PubMed2006

DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy.

BACKGROUND: Adjuvant cisplatin-based chemotherapy improves survival among patients with completely resected non-small-cell lung cancer, but there is no validated clinical or biologic predictor of the benefit of chemotherapy. METHODS: We used immunohistochemical analysis to determine the expression of the excision repair cross-complementation group 1 (ERCC1) protein in operative specimens of non-small-cell lung cancer. The patients had been enrolled in the International Adjuvant Lung Cancer Trial, thereby allowing a comparison of the effect of adjuvant cisplatin-based chemotherapy on survival, according to ERCC1 expression. Overall survival was analyzed with a Cox model adjusted for clinical and pathological factors. RESULTS: Among 761 tumors, ERCC1 expression was positive in 335 (44%) and negative in 426 (56%). A benefit from cisplatin-based adjuvant chemotherapy was associated with the absence of ERCC1 (test for interaction, P=0.009). Adjuvant chemotherapy, as compared with observation, significantly prolonged survival among patients with ERCC1-negative tumors (adjusted hazard ratio for death, 0.65; 95% confidence interval [CI], 0.50 to 0.86; P=0.002) but not among patients with ERCC1-positive tumors (adjusted hazard ratio for death, 1.14; 95% CI, 0.84 to 1.55; P=0.40). Among patients who did not receive adjuvant chemotherapy, those with ERCC1-positive tumors survived longer than those with ERCC1-negative tumors (adjusted hazard ratio for death, 0.66; 95% CI, 0.49 to 0.90; P=0.009). CONCLUSIONS: Patients with completely resected non-small-cell lung cancer and ERCC1-negative tumors appear to benefit from adjuvant cisplatin-based chemotherapy, whereas patients with ERCC1-positive tumors do not.

Adult↗
PubMed2006

Interstitial lung disease in patients with non-small-cell lung cancer treated with epidermal growth factor receptor inhibitors.

Interstitial lung disease (ILD) refers to a diverse range of pulmonary fibrotic disorders and may be hard to accurately diagnose, as distinguishing it from other pulmonary diseases can be difficult. Estimations of the incidence in populations are confounded by the complexity of the different forms of the disorder. In addition, ILD is a comorbid disease of lung cancer and is seen after most forms of chemotherapy and radiotherapy for advanced lung cancer. Incidences of >or=10% have been reported; however, whatever the true incidence, both chemotherapy and radiotherapy enhance the risk of developing ILD. ILD has also been reported with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, including erlotinib (Tarceva, OSI-774) and gefitinib (IRESSA). In a large number of gefitinib-treated patients (n > 185,000) an incidence of approx 1% has been observed (approx 2% in Japan; 0.3% in the rest of the world). Nevertheless, as with other treatments for advanced non-small-cell lung cancer, the clinical benefit outweighs the risk of ILD. In this article, we review the data on ILD with EGFR inhibitors and other common lung cancer treatments.

Carcinoma, Non-Small-Cell Lung↗
PubMed2006

[Neoadjuvant chemotherapy in non small cell lung cancer].

Standards of care for non small cell lung cancer (NSCLC) are not, yet, totally established. The role of induction chemotherapy is still debated while it has been established that adjuvant cisplatin based chemotherapy improve overall survival in completely resected patients. We will review the feasibility and efficacy of induction chemotherapy for patients with early-stage and locally advanced NSCLC, particularly with N2 disease. In the neoadjuvant setting, a 32 to 60% response rate is awaited considering the high treatment compliance. Near to 10% pathologic complete response rate is reported. Nevertheless, no large randomised phase III trial has demonstrated that induction chemotherapy could prolong patients overall survival. Suboptimal cytotoxic combinations and an increased surgical mortality might explain this result. Studies suggested that patient's subgroups (as downstaged N2 disease) could benefit from induction treatment. This still need to be confirmed in randomised trial and meta-analysis based on individual data.

Carcinoma, Non-Small-Cell Lung↗
PubMed2005

Adjuvant chemotherapy for non-small cell lung cancer: contribution of the International Adjuvant Lung Trial.

The recently reported International Adjuvant Lung Cancer Trial (IALT) was designed to assess the potential benefit of three to four cycles of adjuvant cisplatin-based chemotherapy after complete resection of non-small cell lung cancer (NSCLC). Each center predetermined the cisplatin dose (total 300-400 mg/m(2)), the combined drug (etoposide or a Vinca alkaloid), and the radiotherapy policy. From 1995 to 2000, 1,867 patients were randomized in 148 centers from 33 countries. On September 1, 2002, median follow-up was 56 months and >98% of patients had an updated follow-up. Overall survival was significantly different between the two arms: 5-year survival rate was 44.5% in the chemotherapy arm versus 40.4% in the control arm [relative risk = 0.86 (0.76-0.98), P < 0.03]. Disease-free survival, incidence of local recurrence, and incidence of distant metastases (but not brain metastases) were likewise significantly different, with an advantage for the chemotherapy arm. We concluded that adjuvant cisplatin-based chemotherapy in resected NSCLC should become part of the standard management of operable NSCLC. Two other recently reported randomized prospective studies also showed a significant benefit for postoperative platin-based doublets in stage IB and II NSCLC and confirmed the role of adjuvant chemotherapy as part of the treatment of these patients. The Lung Adjuvant Cisplatin Evaluation program, a pooled analysis of all recent platin-based adjuvant trials, and the IALT-Bio study, which will investigate over 30 markers in the IALT patients' specimens, should allow us to better define the populations more likely to benefit from postoperative chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Adjuvant chemotherapy in completely resected non-small-cell lung cancer.

Surgery alone has long been the standard treatment for patients with operable non-small-cell lung cancer (NSCLC). However, despite complete resection, 5-year survival rates have been disappointing, with about 50% of patients eventually suffering relapse and death from disease. Randomized trials conducted in the 1980s hinted at a survival benefit for postoperative cisplatin-based regimens, but they were underpowered. A meta-analysis published in 1995 found a nonsignificant 13% reduction in the risk of death associated with cisplatin-based chemotherapy, with an increase of survival of 5% at 5 years. This led to renewed interest in adjuvant chemotherapy in resected NSCLC. Thousands of patients have been included in a new generation of randomized trials in the last 10 years. Most of these recent studies have now been reported and several have demonstrated a clear survival advantage for patients treated with platin-based adjuvant therapy. These results also suggest a greater benefit with modern two-drug regimens. In view of the most recent data, postoperative platin-based chemotherapy can now be considered the standard of care for completely resected NSCLC patients with good performance status.

Carcinoma, Non-Small-Cell Lung↗
PubMed2005

Treatment of advanced non-small-cell lung cancer in the elderly: results of an international expert panel.

The best treatment for elderly patients with advanced non-small-cell lung cancer (NSCLC) is still debated. To guide clinical management of these patients and suggest the priorities for clinical research in this field, an International Expert Panel met in Naples, Italy, on April 19 to 20, 2004. Results and conclusions based on a review of evidence available in the literature to date are presented in this article. A comprehensive geriatric assessment is recommended to better define prognosis and to predict tolerance to treatment. In the first randomized study dedicated to elderly NSCLC patients, single-agent vinorelbine showed superiority over supportive care alone, both in terms of survival and quality of life. In a large randomized trial, gemcitabine plus vinorelbine failed to show any advantage over either agent alone. Subset analyses suggest that the efficacy of platinum-based combination chemotherapy is similar in fit older and younger patients, with an acceptable increase in toxicity for elderly patients. These data should be interpreted cautiously because retrospective subgroup analyses are encumbered by selection bias; hence, randomized trials dedicated to platinum-based chemotherapy for nonselected elderly patients are warranted. Several promising biologic therapies are under investigation; however, with present data, target-based agents as first-line treatment for elderly NSCLC patients are not yet recommended. Clinical research, with trials specifically designed for elderly patients, is mandatory. With the current evidence, single-agent chemotherapy with a third-generation drug (vinorelbine, gemcitabine, a taxane) should be the recommended option for nonselected elderly patients with advanced NSCLC. Platinum-based chemotherapy is a viable option for fit patients with adequate organ function. Best supportive care remains important, in addition to chemotherapy or as the exclusive option for patients who are unsuitable for more aggressive treatment.

Age Factors↗
PubMed2005

Chemoprevention of lung cancer.

Lung cancer remains a major cause of mortality worldwide, despite advances in surgery, radiotherapy and chemotherapy. Most patients present with advanced disease, and early detection approaches are still experimental. Chemoprevention strategies are therefore essential. Chemoprevention can be defined as the use of specific natural or synthetic chemical agents to reverse, suppress or prevent progression to invasive cancer. The present review will provide an update on lung cancer clinical chemoprevention trials as well as the molecular basis of lung carcinogenesis. A better knowledge of lung carcinogenesis is obviously fundamental to improve chemoprevention strategies. Identification of molecular defects involved in premalignant lesions and/or invasive cancer could lead to clinical studies with new molecular-targeted agents (mainly tyrosine kinase inhibitors, farnesyl-transferase inhibitors and/or antiangiogenic molecules) and the development of surrogate biomarkers. Such biomarkers would be essential to detect high-risk patients, select adequate chemoprevention strategies and monitor drug efficacy. New chemoprevention trials are planned with collaborative efforts of researchers involved in fundamental or clinical studies.

Anticarcinogenic Agents↗
PubMed2005

Epidermal growth factor receptor, HER-2/neu and related pathways in lung adenocarcinomas with bronchioloalveolar features.

Lung adenocarcinomas with bronchioalveolar features (ABAF), formerly called bronchioloalveolar cancers (BAC), constitute a distinct clinical, radiological and pathological entity among lung malignancies. Epidermal growth factor receptor (EGFR) and to a less extent, HER-2/neu, are known to be overexpressed in non-small lung cancers, but their exact status in ABAF is not well-documented. Stimulation of these two receptors results in the initiation of two major cascades, namely phosphatidylinositol 3-kinase (PI-3K) and Ras-dependent pathways. We have therefore studied the expressions of EGFR, HER-2/neu as well as phosphorylated AKT (pAKT) and phosphorylated extracellular-signal regulated kinase (ERK), which are key molecules in these two pathways, in 15 ABAF patients. EGFR was found to be overexpressed in 9 of 15 patients (60%). HER-2/neu overexpression was detected in 6 of the 14 tumors tested (43%). pAKT and pERK were both found to be positive in 13 of 15 patients (87%). Six of the seven tumors with mucinous pattern were negative for EGFR, while all of the other eight cases were positive (P=0.001). Mucinous tumors were also less likely than non-mucinous tumors to overexpress HER-2/neu (17% versus 63%, respectively). These findings suggest that ABAF, particularly those with non-mucinous histology, commonly harbors EGFR and HER-2/neu overexpression. PI-3K and Ras-dependant pathways that lie downstream are generally activated, even in the absence of EGFR and/or HER-2/neu overexpression. ABAF may be a particularly promising candidate for EGFR-targeted strategies and this possibility merits extensive evaluation in clinical trials.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed2005

Should adjuvant chemotherapy become standard treatment in all patients with resected non-small-cell lung cancer?

Surgery remains the main curative treatment for patients with early-stage non-small-cell lung cancer (NSCLC); however, because many patients probably have undetectable micrometastasis even at diagnosis, adjuvant treatment is usually needed. The results for radiotherapy have mostly been disappointing, and a strong emphasis has, therefore, been placed on chemotherapy as the preferred modality. Adjuvant chemotherapy, and in particular, platinum-based regimens, have been assessed in several studies, but the results have been conflicting. Most trials have included patients with a wide range of disease stages and have shown, at most, only moderate improvements in survival. Thus, although clearly indicated in some patients, whether adjuvant chemotherapy should be used in all patients with resected disease is highly controversial. In this debate, Thierry Le Chevalier and colleagues and Giorgio Scagliotti present opposing arguments for whether this approach should be considered standard.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Cutaneous side-effects of kinase inhibitors and blocking antibodies.

Although kinase inhibitors raise hope for people with cancer, patients and their clinicians are commonly confronted with the cutaneous side-effects that are associated with the use of these drugs. This review is the result of collaborations between dermatologists, medical oncologists, and pathologists, and discusses the cutaneous side-effects seen after treatment with the inhibitors of epidermal-growth-factor receptor (EGFR), imatinib, sorafenib, and sunitinib. Some of the side-effects caused by these agents are very distressing, partly because they are chronic owing to the long duration of treatment. Therefore, patients need early and appropriate dermatological management. Moreover, several studies have reported a link between the antitumour efficacy of EGFR inhibitors and cutaneous side-effects. Elucidation of this connection could lead to the identification of crucial predictive factors for tumour response.

Antibodies, Blocking↗
PubMed2005

Adjuvant chemotherapy in early-stage non-small cell lung cancer.

Approximately 80% of lung malignancies are non-small cell lung carcinoma (NSCLC). Patients diagnosed with early-stage disease (about 30% of patients) undergo surgery, but up to 50% develop local or distant recurrence. In an effort to improve survival for patients with resectable NSCLC, chemotherapy has been explored in the adjuvant setting. Several adjuvant trials were launched in the mid 1990s after an individual data-based meta-analysis suggested a 5% survival benefit at 5 years. Among those, the International Adjuvant Lung Cancer Trial (IALT) study, with 1,867 patients included, confirmed the benefit of postoperative chemotherapy in resected NSCLC. More recently, modern platinum-containing doublets showed a 10% to 15% overall benefit compared to no adjuvant treatment. In this article, the current status of adjuvant chemotherapy is reviewed, and future prospects are discussed.

Biomarkers, Tumor↗
PubMed2005

Results of two randomized trials evaluating adjuvant anthracycline-based chemotherapy in 1146 patients with early breast cancer.

Two randomized trials evaluated the effect of 6 courses of anthracycline-based chemotherapy in early breast cancer. A total of 1146 patients were included: 311 high-risk node-negative premenopausal patients and 835 high-risk node-negative or node-positive postmenopausal patients. Patients were randomized after surgery to receive either no chemotherapy (control group) or 6 courses of anthracycline-based chemotherapy (CT group). Postmenopausal patients received adjuvant tamoxifen for at least two years. Radiotherapy was delivered after completion of chemotherapy in the CT group. The 10-year disease-free survival (DFS) rates were 60% in the control group and 65% in the CT group (log-rank test, p = 0.01). The 10-year distant metastasis rates were 28% and 23% (p = 0.02), and the 10-year local recurrence rates were 12% and 10%, respectively (p = 0.24). Chemotherapy was significantly less effective in post-menopausal patients with estrogen receptor-positive tumors. Adjuvant anthracycline-based chemotherapy yielded a significant benefit for DFS by lowering the risk of distant metastases. After up to 10 years of follow-up, deferring radiotherapy after chemotherapy did not compromise local control.

Adult↗
PubMed2005

Tirapazamine with cisplatin and vinorelbine in patients with advanced non-small-cell lung cancer: a phase I/II study.

This phase I/II study was conducted to evaluate the safety and efficacy of tirapazamine in combination with cisplatin and vinorelbine for patients with advanced-stage IIIB/IV chemonaive non-small-cell lung cancer. Seventy patients with a Karnofsky performance status of > or = 60% were included. In the phase I part of the study, 21 patients were treated on day 1 with tirapazamine (escalating doses of 260, 330, or 390 mg/m(2)), cisplatin (75 or 100 mg/m(2)), and vinorelbine (25 or 30 mg/m(2)) for a maximum of 6 cycles every 4 weeks. Vinorelbine was repeated every week. In the phase II part of the study, 49 patients were treated on day 1 with tirapazamine 390 mg/m(2), cisplatin 100 mg/m(2), and vinorelbine 30 mg/m(2). The maximum tolerated dose was not reached. Muscle cramps, vomiting, nausea, tinnitus, neutropenia, and diarrhea were the most frequently reported adverse events in the phase I part of the study. Most of these events were grade 1 or 2. In the phase II part of the study, response rate was 47%, and median survival was 50 weeks. The most frequently reported adverse event was neutropenia. Asthenia, fever, anemia, vomiting, weight decrease, nausea, and muscle cramps were also noted. For patients treated at the maximum dose, dose reductions occurred 14% of tirapazamine cycles and in 4% of cisplatin cycles. The median number of cycles was 3. This regimen has a manageable toxicity profile. Response rate and median survival suggest that this combination might be more active than the cisplatin/vinorelbine combination. This triplet is currently being evaluated in a phase III study.

Adult↗
PubMed2004

Nuclear localization of apoptosis protease activating factor-1 predicts survival after tumor resection in early-stage non-small cell lung cancer.

The proapoptotic protein apoptosis protein activating factor-1 (Apaf-1), which is normally located in the cytoplasm, can translocate to the nucleus before non-small cell lung carcinoma (NSCLC) cells manifest signs of apoptosis such as mitochondrial damage, caspase activation, or chromatin condensation. This may indicate a stage of imminent apoptosis. Importantly, we found that 24% (15 of 62) of resected stage I NSCLC (T(1)N(0)M(0) or T(2)N(0)M(0)), manifested a marked nuclear localization of Apaf-1 (Apaf-1(Nuc)), as compared with the mostly cytoplasmic localization of Apaf-1 found in the remaining tumors (Apaf-1(Cyt)). After a median follow-up of 6.31 years, the actuarial 5-year overall survival rates were 89% (56-98%) in the Apaf-1(Nuc) group and 54% (36-71%) in the Apaf-1(Cyt) group (P = 0.039). No correlation between the subcellular localization of Apaf-1 and that of p53 and Hsp70 could be established. Thus, the subcellular location of Apaf-1 (but not that of p53 or Hsp70) constitutes an accurate prognostic factor for overall survival in NSCLC.

Adult↗
PubMed2004

Phase II study of pemetrexed-gemcitabine combination in patients with advanced-stage non-small cell lung cancer.

PURPOSE: Cisplatin is one of the most active agents for the treatment of non-small cell lung cancer (NSCLC). It is also known for significant toxicity, which makes it unsuitable for certain patients. Our purpose was to evaluate the efficacy and toxicity of a promising cisplatin-free combination, gemcitabine plus pemetrexed, in NSCLC. EXPERIMENTAL DESIGN: Chemo-naive patients with inoperable NSCLC were eligible for this study. Gemcitabine (1250 mg/m2) was given intravenously on days 1 and 8, followed by intravenous pemetrexed (500 mg/m2) on day 8. After inclusion of 13 patients, folic acid and vitamin B12 supplementation was added to lower pemetrexed-induced toxicity. Quality of life was assessed with the Lung Cancer Symptom Scale. RESULTS: Sixty patients enrolled; 58 were evaluable for response. All patients had a World Health Organization performance status of 0 or 1. Eighty-seven percent had stage IV disease. Nine patients had a confirmed partial response [overall response rate, 15.5%; 95% confidence interval (CI), 7.3-27.4%]. Twenty-nine (50.0%) patients had stable disease. Median overall survival was 10.1 months (95% CI, 7.9-13.0 months), with a 1- and 2-year overall survival of 42.6% (95% CI, 30.0-55.3%) and 18.5% (95% CI, 7.9-29.1%). Median progression-free survival was 5.0 months. Median response duration was 3.3 months. There were no deaths attributed to treatment. Common Toxicity Criteria grade 3/4 toxicities were neutropenia (61.7%), febrile neutropenia (16.7%), fatigue (23.3%), and elevations of aspartate aminotransferase (15.0%) and alanine aminotransferase (20.0%). CONCLUSIONS: This combination had good tolerance and achieved promising overall survival with extended 1- and 2-year survival rates. This cisplatin-free regimen warrants further evaluation in randomized trials.

Adult↗